In general, crystalline forms of drugs are utilized in dosage forms rather than amorphous forms of drugs, in part, because of their superior stability. For example, in many situations, an amorphous drug converts to a crystalline drug form upon storage. Because amorphous and crystalline forms of a drug typically have different physical properties, chemical properties, potencies and/or bioavailabilities, such interconversion is undesirable for safety reasons in pharmaceutical administration.
Polymorphs are crystals of the same molecule which have different physical properties because the crystal lattice contains a different arrangement of molecules. For example, certain polymorphs can include different hydration states that incorporate water into the crystalline structure without chemical alteration of the molecule itself. In that regard, certain compounds can exist in anhydrous and hydrated forms, where the hydrated forms can include, for example, hydrates, dihydrates, trihydrates, and the like, or partial hydrates such as hemihydrates. The different physical properties exhibited by polymorphs can affect important pharmaceutical parameters such as storage, stability, compressibility, density (which is important in formulation and product manufacturing) and dissolution rates (which are important in determining bioavailability). Stability differences may result from changes in chemical reactivity (e.g., differential hydrolysis or oxidation, such that a dosage form discolors more rapidly when the dosage form comprises one polymorph rather than another polymorph), mechanical changes (e.g., tablets crumble on storage as a kinetically favored crystalline form converts to a thermodynamically more stable crystalline form) or both (e.g., tablets of one polymorph are more susceptible to breakdown at high humidity). Solubility differences between polymorphs may, in extreme situations, result in transitions to crystalline forms that lack potency and/or are toxic. In addition, the physical properties of a particular crystalline form may be important in pharmaceutical processing. For example, one particular crystalline form may form solvates more readily or may be more difficult to filter and wash free of impurities than other forms (e.g., particle shape and size distribution might be different between one crystalline form relative to other forms).
Regulatory agencies such as the United States Food and Drug Administration closely regulate the polymorphic content of the active component of a drug in solid dosage forms. In general, regulatory agencies require batch-by-batch monitoring for polymorphic drugs if anything other than the pure, thermodynamically preferred polymorph is marketed. Accordingly, medical and commercial reasons favor synthesizing and marketing the most thermodynamically stable polymorph of a crystalline drug substance in solid drugs, which is substantially free of other, less favored polymorphs.
(N, N-Diethylcarbamoyl)methyl methyl (2E)but-2-ene-1,4-dioate (1) has the following chemical structure:

Compound (1) is a prodrug of methyl hydrogen fumarate. Once administered, the compound is metabolized in vivo into an active metabolite, namely, methyl hydrogen fumarate (MHF) which is also referred to herein as monomethyl fumarate (MMF). The in vivo metabolism of (N,N-Diethylcarbamoyl)methyl methyl (2E)but-2-ene-1,4-dioate to MHF/MMF is illustrated below:

Compound (1) is synthesized in Example 1 of Gangakhedkar et al. U.S. Pat. No. 8,148,414 and is disclosed as having a melting point between 53° C. and 56° C. Oral dosage forms comprising compound (1) are disclosed in U.S. patent application Ser. No. 13/973,456 filed Aug. 22, 2013, and Ser. No. 13/973,622 filed Aug. 22, 2013. High drug load formulations of compound (1) are disclosed in U.S. patent application Ser. No. 13/973,542 filed Aug. 22, 2013. Therapeutic uses and methods of treatment for compound (1) are disclosed in U.S. patent application Ser. No. 13/973,820 filed Aug. 22, 2013, Ser. No. 13/906,155 filed May 30, 2013, Ser. No. 13/973,700 filed Aug. 22, 2013, and 13,973,780 Aug. 22, 2013. Methods of making compound (1) are disclosed in U.S. patent application Ser. No. 14/298,713 filed Jun. 6, 2014. The contents of each of the above referenced patents and patent applications are hereby incorporated by reference in their entireties.
Co-crystalline forms of (N,N-Diethylcarbamoyl)methyl methyl (2E)but-2-ene-1,4-dioate with different co-formers are disclosed in U.S. patent application Ser. No. 14/072,138 filed Nov. 5, 2013, the contents of which is hereby incorporated by reference in its entirety.